In vitro fertilization (IVF) techniques have been available for many years and IVF is the most effective form of assisted reproductive technology. However, IVF success rates are low, with live birth rates ranging from about 40% for women under 35 to about 4% for women over 42. Many factors influence the success rate, including maternal age, duration of infertility or subfertility, number of oocytes, hormone levels, body mass index, endometrium characteristics, and semen quality. Failure to achieve proper implantation of the blastocyst is one of the major issues in both natural and assisted reproduction.
Adrenomedullin (Adm gene, AM protein) is a peptide vasodilator that is elevated nearly five-fold in healthy human pregnancies but often blunted in pregnancies that are complicated by fetal growth restriction, gestational diabetes, or preeclampsia. Polymorphisms in the genes encoding AM peptide or its G protein-coupled receptor CLR have been shown to be associated with poor pregnancy outcomes, including altered birth weight, gestational diabetes, and preeclampsia (Lenhart et al., Am. J. Perinatol. 31:327 (2014)). Moreover, studies have demonstrated that plasma concentrations of MR-proADM (a proteolytic byproduct and surrogate of AM peptide) are blunted in severe preeclampsia and that MR-proADM is similarly effective as other common preeclampsia biomarkers (endoglin and placental growth factor) at discriminating between patients with severe preeclampsia and normotensive patients (Matson et al., Placenta 35:780 (2014)). Therefore, maintaining high levels of AM peptide signaling during human pregnancy is critical for good maternal and fetal clinical outcomes (Lenhart et al., Trends Endocrinol. Metab. 23:524 (2012)).
Using gene-targeted mouse models, it has been shown that haploinsufficiency for maternal AM leads to poor uterine receptivity, reduced pinopode formation, and subfertility (Li et al., Biol. Reprod. 79:1169 (2008)). Pregnant Adm+/− females exhibit abnormal implantation spacing, ectopic placentation, and fetal growth restriction that is largely independent of fetal genotype (Li et al., J. Clin. Invest. 116:2653 (2006)). These data indicate that a modest genetic reduction in maternal levels of AM is sufficient to cause pregnancy complications. Although Adm+/− mice die at mid-gestation with lymphatic vascular defects (Fritz-Six et al., J. Clin. Invest. 118:40 (2008)), it has recently been discovered that fetal AM is required for branching morphogenesis of the placental labyrinth layer and remodeling of maternal spiral arteries. Adm+/− fetal vessels are larger and under-branched compared to those of their wildtype littermates. The maternal spiral arteries which feed the Adm+/− placenta fail to remodel compared to the spiral arteries of neighboring Adm+/+ placentas. Importantly, these phenotypes are reversed in a genetic model with 3-fold overexpression of fetal AM. Concomitantly, a marked reduction in uterine natural killer (uNK) cells was found along with a significant change in the placental chemokine and cytokine profile of Adm+/− placentas. Furthermore, in response to AM treatment, uNK cells secrete a variety of chemokines and cytokines that work to increase MMP9 activity and induce smooth muscle cell apoptosis. Therefore, AM serves as a trophoblast-derived factor that is critical for fetal placental vascularization and for enabling the maternal vascular adaptation to pregnancy to protect against preeclampsia (Li et al., J. Clin. Invest. 123:2408 (2013)).
There is a need in the art for new methods for enhancing fetal implantation and increasing the success rate of in vitro fertilization.